Unexpected Steric Effects of “Remote” Alkyl Groups on the Rate of Conjugate Additions to Alkyl α,β-Ethylenic Sulfones, Sulfoxides, and Esters

Examination of conjugated ethylenic sulfones, sulfoxides, and esters in Michael-type addition reactions reveals, for the first time, that the size of the heteroatom-attached alkyl group affects the rate of conjugate addition. Molecular modeling strongly suggests that what are generally considered to be “remote” alkyl groups in −CβHCαHS(O)nalkyl systems and −CH2CβHCαHCOOalkyl systems are actually not remote from the β-carbon atom of the Michael accepting unit. Molecular modeling clearly shows that the alkyl groups in these Michael acceptors shield the β-carbons in the following order:  Et i-Pr < t-Bu. Competition experiments establish the relative rates of Michael additions to be in the following order:  Et > i-Pr > t-Bu

Homolog of tocopherol C methyltransferases catalyzes N methylation in anticancer alkaloid biosynthesis

Madagascar periwinkle (Catharanthus roseus) is the sole source of the anticancer drugs vinblastine and vincristine, bisindole alkaloids derived from the dimerization of the terpenoid indole alkaloids vindoline and catharanthine. Full elucidation of the biosynthetic pathways of these compounds is a prerequisite for metabolic engineering efforts that will improve production of these costly molecules. However, despite the medical and commercial importance of these natural products, the biosynthetic pathways remain poorly understood. Here we report the identification and characterization of a C. roseus cDNA encoding an S-adenosyl-L-methionine-dependent N methyltransferase that catalyzes a nitrogen methylation involved in vindoline biosynthesis. Recombinant enzyme produced in Escherichia coli is highly substrate specific, displaying a strict requirement for a 2,3-dihydro bond in the aspidosperma skeleton. The corresponding gene transcript is induced in methyl jasmonate-elicited seedlings, along with the other known vindoline biosynthetic transcripts. Intriguingly, this unique N methyltransferase is most similar at the amino acid level to the plastidic ?-tocopherol C methyltransferases of vitamin E biosynthesis, suggesting an evolutionary link between these two functionally disparate methyltransferases

Biocatalytic asymmetric formation of tetrahydro-β-carbolines

Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon-carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-ß-carboline moiety - an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-ß-carboline enantiomers are greatly valued. We report that strictosidine synthase from Ophiorrhiza pumila utilizes a range of simple achiral aldehydes and substituted tryptamines to form highly enantioenriched (ee >98%) tetrahydro-ß-carbolines via a Pictet-Spengler reaction. This is the first example of aldehyde substrate promiscuity in the strictosidine synthase family of enzymes and represents a first step towards developing a general biocatalytic strategy to access chiral tetrahydro-ß-carbolines

Malaria-Infected Mice Are Cured by Oral Administration of New Artemisinin Derivatives

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 × 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6–7 postinfection. At only 3 × 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14–17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7–13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials

Mechanistic advances in plant natural product enzymes

The biosynthetic pathways of plantnaturalproducts offer an abundance of knowledge to scientists in many fields. Synthetic chemists can be inspired by the synthetic strategies that nature uses to construct these compounds. Chemical and biological engineers are working to reprogram these biosynthetic pathways to more efficiently produce valuable products. Finally, biochemists and enzymologists are interested in the detailed mechanisms of the complex transformations involved in the construction of these naturalproducts. Study of biosynthetic enzymes and pathways therefore has a wide-ranging impact. In recent years, many plant biosynthetic pathways have been characterized, particularly the pathways that are responsible for alkaloid biosynthesis. Here we highlight recently studied alkaloid biosynthetic enzymes that catalyze production of numerous complex medicinal compounds, as well as the specifier proteins in glucosinosolate biosynthesis, whose structure and mechanism of action are just beginning to be unraveled